The objective is to isolate all of the neuroleptic active principles of Saururus cernuus, determine their structures, and evaluate them for their neuroleptic profile. Accordingly, from the active fraction of the extract, 12 neolignoid components were isolated. Of these, the major active principle was named manassantin A (MNS, giver of peace of mind), with manassantin B being less potent. The structures of all but one of the 12 lignoid components were determined. Manassantins A and B are the first examples of the novel dineolignan class. Preliminary evaluation showed that MNS behaved as a neuroleptic: blocked amphetamine stereotypy, amphetamine and aggregation-induced toxicity, conditioned avoidance response; produced hypothermia and caused release of prolactin. However, it showed no catalepsy or ptosis; interacted only weakly (IC 50 10-5M) with dopamine (DA) receptors and did not affect DA stimulated adenylate cyclase. Thus, these properties suggested that MNS does have neuroleptic activity but that it acts as an atypical neuroleptic. Since atypical neuroleptics are much sought-after drugs and since MNS has structure different from any other known neuroleptic (nonbasic and has no nitrogen), more detailed studies are warranted. One property, a relatively low LD50, is a drawback for MNS, if it were ever to be considered as a therapeutic agent. Hence, the following specific aims are proposed for this grant: 1. Determine the mechanism of action of MNS based on the commonly used parameters such as: (a) blockage of the various apomorphine-induced behavioral symptoms, (b) binding to receptors of not only the DA but also, alpha 1, alpha 2 adrenergic, seratonergic, cholinergic (and even opiate) type and (c) study the effects of MNS on DA synthesis, release and turnover. 2. Elucidate the metabolic disposition of MNS by (a) providing important pharmacokinetic parameters, (b) studying tissue distribution and (c) isolating and evaluating the activity of metabolites. 3. Generate some specific analogues which retain the atypical neuroleptic profile but with a better therapeutic index. This effort includes synthesis of MNS and its close structural and stereochemical analogues; prodrug types such as esters, oxidation and reduction products; soft drug types based on the metabolite approach, and analogues with specific brain-delivery capability. All 3 of these objectives are expected not only to provide data to evaluate MNS (or its analogue) as a useful therapeutic agent, but also new leads on the mode of action of neuroleptics in general.